The present invention relates to the field of ophthalmology. More specifically, the invention relates to the field of glaucoma filtration surgery.
The underlying causes of glaucoma are not fury understood. However, it is known that a principal symptom of this disease is elevated intraocular pressure. Elevations of intraocular pressure can ultimately lead to impairment or loss of normal visual function as a result of damage to the optic nerve. It is also known that the elevated intraocular pressure is caused by an excess of fluid (i.e., aqueous humor) within the eye. The excess intraocular fluid is believed to result from blockage or impairment of the normal drainage of fluid from the eye via the trabecular meshwork.
The current drug therapies for treating glaucoma attempt to control intraocular pressure by means of increasing the drainage or "outflow" of aqueous humor from the eye or decreasing the production or "inflow" of aqueous humor in the ciliary processes of the eye. Unfortunately, the use of drug therapy alone is not sufficient to adequately control intraocular pressure in some patients, particularly if there is a severe blockage of the normal passages for the outflow of aqueous humor. Such patients may require surgical intervention to restore the normal outflow of aqueous humor and thereby normalize or at least control their intraocular pressure. The outflow of aqueous humor can be improved by means of various intraocular surgical procedures known to those skilled in the art, such as trabeculectomy, posterior lip sclerectomy, trephine and thermal sclerostomy. These surgical procedures are collectively referred to herein as "glaucoma filtration surgery".
The procedures utilized in glaucoma filtration surgery generally involve the creation of a fistula to promote the drainage of aqueous humor. Although various procedures have been utilized, the procedures will typically include the creation of an elevation of the conjunctiva at the surgical site. This elevation is commonly referred to as the "filtering bleb". The filtering blebs which are most often associated with good intraocular pressure control are avascular and either low and diffuse or elevated with numerous cystic spaces. Studies have suggested that aqueous fluid in the filtering bleb usually filters through the conjunctiva and mixes with the tear film, or is adsorbed by vascular or perivascular conjunctival tissue.
Although glaucoma filtration surgery is generally successful initially, it is ultimately plagued in many cases by the formation of scar tissue which blocks the fistula created during the surgery. The following articles may be referred to for further background information concerning this problem:
1) Tahery, M. M., et at., "Pharmacologic Control of Wound Healing in Glaucoma Filtration Surgery", Journal of Ocular Pharmacology, Vol. 5, No. 2, pages 155-179 (1989);
2) Tripathi, R. C., "Growth Factors in the Aqueous Humor and Their Therapeutic Implications in Glaucoma and Anterior Segment Disorders of the Human Eye", Drug Development Research, Vol. 22, pages 1-23 (1991); and
3) Textbook of Glaucoma (2nd ed.), ed. M. Bruce Shields, M.D., "Glaucoma Filtering Procedures", Chapter 34, pages 461-487, Baltimore Md.: Williams & Wilkins (1987).
The most common cause of failure in glaucoma filtration surgery is closure of the fistula as the result of scar tissue formation and other manifestations of the normal wound healing process. The increased amount of collagen in the failed fistulas suggests that proliferation of fibroblasts and associated production of extracellular matrix materials, particularly collagen, fibronectin and glycosaminoglycans, may lead to fistula failure.
As indicated in the above-cited article by Tahery, et at., the use of drugs to inhibit or control the wound healing process, and thereby limit the formation of scar tissue in glaucoma filtration surgery, has been previously proposed. The article mentions various types of drugs as potential inhibitors of the wound healing process, including anti-inflammatory drugs and anti-proliferative drugs. However, the use of such drugs to prevent scar formation associated with glaucoma filtration surgery has had very limited success. One reason for this lack of success is that the wound healing process does not take place instantaneously. Consequently, it is not possible to simply prevent scar formation by means of a single application of the drugs mentioned by Tahery, et al., at the time of surgery. Moreover, many of those drugs, when utilized to prevent scar formation, are inherently toxic to ophthalmic tissues other than the tissues directly involved in the surgically induced wound healing process, particularly at higher concentrations. This potential toxicity precludes the use of high drag concentrations which might otherwise be considered desirable in order to control or at least suppress the formation of extracellular matrix materials and scar tissue associated with wound closure following glaucoma filtration surgery. Moreover, even with the use of antiproliferative agents such as 5'-fluorouracil, the failure rate (i.e., total blockage of fistula) in high-risk groups, such as patients with previous failed filtering surgery, previous cataract extraction, aphakia, or neovascular glaucoma, is still significant. In addition, many of the antiproliferative drugs used may be associated with complications such as corneal or conjunctival epithelial loss, corneal opacification, and wound leaks, and the possibility of long-term leaks and endophthalmitis related to extremely thin blebs which can occur with drug treatment. The use of single-dose, intra-operative exposures to antiproliferative agents such as mitomycin C may reduce some of these problems, but the problems with thin blebs and hypotony will still exist.
In view of the foregoing circumstances, there is a need for an improved drug therapy to complement glaucoma filtration surgery, so that the improved outflow of aqueous humor achieved by means of the surgery is not ultimately lost as the result of closure of the surgical fistula by scar tissue. The present invention is directed to satisfying this need.